Self-amplifying NRF2–EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer

Hayes, J. D., Dinkova-Kostova, A. T. & Tew, K. D. Oxidative stress in cancer. Cancer Cell 38, 167–197 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Principe, D. R. et al. The current treatment paradigm for pancreatic ductal adenocarcinoma and barriers to therapeutic efficacy. Front. Oncol. 11, 688377 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Xu, Y., Liu, J., Nipper, M. & Wang, P. Ductal vs. acinar? Recent insights into identifying cell lineage of pancreatic ductal adenocarcinoma. Ann. Pancreat. Cancer 2, 11 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Kopp, J. L. et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22, 737–750 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).

Article  CAS  PubMed  Google Scholar 

Tabata, T., Fujimori, T., Maeda, S., Yamamoto, M. & Saitoh, Y. The role of ras mutation in pancreatic cancer, precancerous lesions, and chronic pancreatitis. Int. J. Pancreatol. 14, 237–244 (1993).

Article  CAS  PubMed  Google Scholar 

Tada, M. et al. Analysis of K-RAS gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease. Gastroenterology 110, 227–231 (1996).

Article  CAS  PubMed  Google Scholar 

Becker, A. E., Hernandez, Y. G., Frucht, H. & Lucas, A. L. Pancreatic ductal adenocarcinoma: risk factors, screening, and early detection. World J. Gastroenterol. 20, 11182–11198 (2014).

Article  PubMed  PubMed Central  Google Scholar 

Pandol, S. J., Gorelick, F. S. & Lugea, A. Environmental and genetic stressors and the unfolded protein response in exocrine pancreatic function—a hypothesis. Front. Physiol. 2, 8 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Makohon-Moore, A. & Iacobuzio-Donahue, C. A. Pancreatic cancer biology and genetics from an evolutionary perspective. Nat. Rev. Cancer 16, 553–565 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Xia, D. et al. NADPH oxidase 1 mediates caerulein-induced pancreatic fibrosis in chronic pancreatitis. Free Radic. Biol. Med. 147, 139–149 (2020).

Article  CAS  PubMed  Google Scholar 

Carriere, C., Young, A. L., Gunn, J. R., Longnecker, D. S. & Korc, M. Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras. Biochem. Biophys. Res. Commun. 382, 561–565 (2009).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yamaguchi, J., Yokoyama, Y., Kokuryo, T., Ebata, T. & Nagino, M. Cells of origin of pancreatic neoplasms. Surg. Today 48, 9–17 (2018).

Article  PubMed  Google Scholar 

Perera, R. M. & Bardeesy, N. Pancreatic cancer metabolism: breaking it down to build it back up. Cancer Discov. 5, 1247–1261 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Del Poggetto, E. et al. Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis. Science 373, eabj0486 (2021).

Article  PubMed  PubMed Central  Google Scholar 

Li, Y. et al. Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer. Nat Cancer 2, 49–65 (2021).

Article  CAS  PubMed  Google Scholar 

Margueron, R. & Reinberg, D. The Polycomb complex PRC2 and its mark in life. Nature 469, 343–349 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kim, K. H. & Roberts, C. W. Targeting EZH2 in cancer. Nat. Med. 22, 128–134 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Escobar, T. M. et al. Active and repressed chromatin domains exhibit distinct nucleosome segregation during DNA replication. Cell 179, 953–963 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bracken, A. P. et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 22, 5323–5335 (2003).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mallen-St Clair, J. et al. EZH2 couples pancreatic regeneration to neoplastic progression. Genes Dev. 26, 439–444 (2012).

Article  PubMed  PubMed Central  Google Scholar 

Chen, N. M. et al. Context-dependent epigenetic regulation of nuclear factor of activated T cells 1 in pancreatic plasticity. Gastroenterology 152, 1507–1520 (2017).

Article  CAS  PubMed  Google Scholar 

Patil, S. et al. EZH2 regulates pancreatic cancer subtype identity and tumor progression via transcriptional repression of GATA6. Cancer Res. 80, 4620–4632 (2020).

Article  CAS  PubMed  Google Scholar 

Ma, Q. Role of NRF2 in oxidative stress and toxicity. Annu. Rev. Pharmacol. Toxicol. 53, 401–426 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chio, I. I. C. et al. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. Cell 166, 963–976 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

DeNicola, G. M. et al. Oncogene-induced NRF2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sullivan, L. B. & Chandel, N. S. Mitochondrial reactive oxygen species and cancer. Cancer Metab 2, 17 (2014).

Article  PubMed  PubMed Central  Google Scholar 

Todoric, J. et al. Stress-activated NRF2–MDM2 cascade controls neoplastic progression in pancreas. Cancer Cell 32, 824–839 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Singh, A. et al. Small molecule inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors. ACS Chem. Biol. 11, 3214–3225 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Torrente, L. & DeNicola, G. M. Targeting NRF2 and its downstream processes: opportunities and challenges. Annu. Rev. Pharmacol. Toxicol. 62, 279–300 (2022).

Article  CAS 

Comments (0)

No login
gif